14-3-3sigma regulates B-cell homeostasis through stabilization of FOXO1

Yu-Wen Su; Zhenyue Hao; Atsushi Hirao; Kazuo Yamamoto; Wen-Jye Lin; Ashley Young; Gordon S Duncan; Hiroki Yoshida; Andrew Wakeham; Philipp A Lang; Kiichi Murakami; Heiko Hermeking; Bert Vogelstein; Pamela Ohashi; Tak W Mak

doi:10.1073/pnas.1017729108

14-3-3sigma regulates B-cell homeostasis through stabilization of FOXO1

Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1555-60. doi: 10.1073/pnas.1017729108. Epub 2011 Jan 4.

Authors

Yu-Wen Su¹, Zhenyue Hao, Atsushi Hirao, Kazuo Yamamoto, Wen-Jye Lin, Ashley Young, Gordon S Duncan, Hiroki Yoshida, Andrew Wakeham, Philipp A Lang, Kiichi Murakami, Heiko Hermeking, Bert Vogelstein, Pamela Ohashi, Tak W Mak

Affiliation

¹ Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1.

Abstract

14-3-3σ regulates cytokinesis and cell cycle arrest induced by DNA damage but its role in the immune system is unknown. Using gene-targeted 14-3-3σ-deficient (i.e., KO) mice, we studied the role of 14-3-3σ in B-cell functions. Total numbers of B cells were reduced by spontaneous apoptosis of peripheral B cells. Upon B-cell antigen receptor engagement in vitro, KO B cells did not proliferate properly or up-regulate CD86. In response to T cell-independent antigens, KO B cells showed poor secretion of antigen-specific IgM. This deficit led to increased lethality of KO mice after vesicular stomatitis virus infection. KO B cells showed elevated total FOXO transcriptional activity but also increased FOXO1 degradation. Coimmunoprecipitation revealed that endogenous 14-3-3σ protein formed a complex with FOXO1 protein. Our results suggest that 14-3-3σ maintains FOXO1 at a consistent level critical for normal B-cell antigen receptor signaling and B-cell survival.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

14-3-3 Proteins / genetics
14-3-3 Proteins / immunology*
14-3-3 Proteins / metabolism
Adoptive Transfer
Animals
Antigens / immunology
Apoptosis / immunology
B-Lymphocytes / cytology
B-Lymphocytes / immunology*
B-Lymphocytes / metabolism
Blotting, Western
Cell Proliferation
Cells, Cultured
Enzyme-Linked Immunosorbent Assay
Female
Ficoll / analogs & derivatives
Ficoll / immunology
Forkhead Box Protein O1
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / immunology*
Forkhead Transcription Factors / metabolism
Homeostasis / immunology*
Immunoglobulin G / blood
Immunoglobulin M / blood
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Protein Binding
Receptors, Antigen, B-Cell / immunology
Reverse Transcriptase Polymerase Chain Reaction
Trinitrobenzenes / immunology

Substances

14-3-3 Proteins
Antigens
Forkhead Box Protein O1
Forkhead Transcription Factors
Foxo1 protein, mouse
Immunoglobulin G
Immunoglobulin M
Receptors, Antigen, B-Cell
Sfn protein, mouse
TNP-ficoll
Trinitrobenzenes
Ficoll